Genomes and Genes
Summary: Tumor suppressor genes located on human chromosome 9 in the region 9p21. This gene is either deleted or mutated in a wide range of malignancies. (From Segen, Current Med Talk, 1995) Two alternatively spliced gene products are encoded by p16: CYCLIN-DEPENDENT KINASE INHIBITOR P16 and TUMOR SUPPRESSOR PROTEIN P14ARF.
- Goldstein A, Chan M, Harland M, Gillanders E, Hayward N, Avril M, et al. High-risk melanoma susceptibility genes and pancreatic cancer, neural system tumors, and uveal melanoma across GenoMEL. Cancer Res. 2006;66:9818-28 pubmed..This GenoMEL study provides the most extensive characterization of mutations in high-risk melanoma susceptibility genes in families with three or more melanoma patients yet available...
- Koscielny S, Dahse R, Ernst G, von Eggeling F. The prognostic relevance of p16 inactivation in head and neck cancer. ORL J Otorhinolaryngol Relat Spec. 2007;69:30-6 pubmed..The inactivation of the tumor suppressor gene p16 plays a role in the carcinogenesis of head and neck cancer. ..
- Zeggini E, Weedon M, Lindgren C, Frayling T, Elliott K, Lango H, et al. Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes. Science. 2007;316:1336-41 pubmed..The regions identified underscore the importance of pathways influencing pancreatic beta cell development and function in the etiology of type 2 diabetes. ..
- McPherson R, Pertsemlidis A, Kavaslar N, Stewart A, Roberts R, Cox D, et al. A common allele on chromosome 9 associated with coronary heart disease. Science. 2007;316:1488-91 pubmed..Homozygotes for the risk allele make up 20 to 25% of Caucasians and have a approximately 30 to 40% increased risk of CHD. ..
- Guerrero D, Guarch R, Ojer A, Casas J, Ropero S, Mancha A, et al. Hypermethylation of the thrombospondin-1 gene is associated with poor prognosis in penile squamous cell carcinoma. BJU Int. 2008;102:747-55 pubmed publisher..status in the promoter region of thrombospondin-1 (TSP-1), RAS association domain family 1A (RASSF1-A) and p16 genes, and the expression of TSP-1, CD31, p16 and p53 proteins in patients diagnosed with penile cancer, and the ..
- Goldstein A, Chaudru V, Ghiorzo P, Badenas C, Malvehy J, Pastorino L, et al. Cutaneous phenotype and MC1R variants as modifying factors for the development of melanoma in CDKN2A G101W mutation carriers from 4 countries. Int J Cancer. 2007;121:825-31 pubmed..Differences in melanoma risk across geographic regions justify the need for individual studies in each country before counseling should be considered. ..
- Chen P, Cheng Y, Chiang C, Tseng S, Chau P, Tsai Y. Hypermethylation of the p16 gene promoter in pterygia and its association with the expression of DNA methyltransferase 3b. Mol Vis. 2006;12:1411-6 pubmed..These data provided molecular evidence that methylation occurs in pterygia and that it may play a role in the their development. ..
- Helgadottir A, Thorleifsson G, Manolescu A, Gretarsdottir S, Blondal T, Jonasdottir A, et al. A common variant on chromosome 9p21 affects the risk of myocardial infarction. Science. 2007;316:1491-3 pubmed..64 times as great as that of noncarriers. The corresponding risk is 2.02 times as great for early-onset cases. The population attributable risk is 21% for MI in general and 31% for early-onset cases. ..
- Hong Y, Roh M, Kim N, Lee H, Kim H, Lee K, et al. Hypermethylation of p16INK4a in Korean non-small cell lung cancer patients. J Korean Med Sci. 2007;22 Suppl:S32-7 pubmed..Other clinicopathological characteristics, including age, sex, tumor stage, and histologic type were not found to be correlated with p16(INK4a) methylation. ..
- Harland M, Goldstein A, Kukalizch K, Taylor C, Hogg D, Puig S, et al. A comparison of CDKN2A mutation detection within the Melanoma Genetics Consortium (GenoMEL). Eur J Cancer. 2008;44:1269-74 pubmed publisher..The relatively low rate of CDKN2A mutation detection is not due to failure to detect mutations and implies the existence of other high penetrance melanoma susceptibility genes. ..
- Roth M, Abnet C, Hu N, Wang Q, Wei W, Green L, et al. p16, MGMT, RARbeta2, CLDN3, CRBP and MT1G gene methylation in esophageal squamous cell carcinoma and its precursor lesions. Oncol Rep. 2006;15:1591-7 pubmed..Balloon cytology may be able to screen the length of the esophagus effectively for a subset of cells with abnormal methylation, and may be useful in a primary screening test for ESCC and its precursor lesions. ..
- Maley C, Galipeau P, Finley J, Wongsurawat V, Li X, Sanchez C, et al. Genetic clonal diversity predicts progression to esophageal adenocarcinoma. Nat Genet. 2006;38:468-73 pubmed..6) and ploidy abnormalities. Progression to cancer through accumulation of clonal diversity, on which natural selection acts, may be a fundamental principle of neoplasia with important clinical implications. ..
- Shaw R, Hall G, Woolgar J, Lowe D, Rogers S, Field J, et al. Quantitative methylation analysis of resection margins and lymph nodes in oral squamous cell carcinoma. Br J Oral Maxillofac Surg. 2007;45:617-22 pubmed..PMA upgraded 13 of the 20 surgical margins, 6 of which subsequently had a recurrent tumour. Not all of these recurrences were predicted and the effects of adjuvant treatment make firm conclusions difficult. ..
- Romanenko A, Morell Quadreny L, Lopez Guerrero J, Pellin A, Nepomnyaschy V, Vozianov A, et al. The INK4a /ARF locus: role in cell cycle control for renal cell epithelial tumor growth after the Chernobyl accident. Virchows Arch. 2004;445:298-304 pubmed..These actions could lead to disruptions and loss of cell cycle checkpoints and, thereby, to cellular transformation...
- Huang H, Illei P, Zhao Z, Mazumdar M, Huvos A, Healey J, et al. Ewing sarcomas with p53 mutation or p16/p14ARF homozygous deletion: a highly lethal subset associated with poor chemoresponse. J Clin Oncol. 2005;23:548-58 pubmed..Alterations in p53 or p16/p14ARF are found in a fourth of ES cases and define a subset with highly aggressive behavior and poor chemoresponse. ..
- Dijkman R, Tensen C, Jordanova E, Knijnenburg J, Hoefnagel J, Mulder A, et al. Array-based comparative genomic hybridization analysis reveals recurrent chromosomal alterations and prognostic parameters in primary cutaneous large B-cell lymphoma. J Clin Oncol. 2006;24:296-305 pubmed..Inactivation of CDKN2A by either deletion or methylation of its promoter could be an important prognostic parameter for the group of PCLBCL, leg type. ..
- Gibson S, Boquoi A, Chen T, Sharpless N, Brensinger C, Enders G. p16(Ink4a) inhibits histologic progression and angiogenic signaling in min colon tumors. Cancer Biol Ther. 2005;4:1389-94 pubmed..01). Exogenous p16 expression in human colon tumor cells in vitro inhibited VEGF production. These results suggest that p16 constrains colon tumor progression, in part through inhibiting angiogenic signaling. ..
- Lang J, Boxer M, MacKie R. CDKN2A mutations in Scottish families with cutaneous melanoma: results from 32 newly identified families. Br J Dermatol. 2005;153:1121-5 pubmed..This study brings the total of Scottish families investigated for germline mutations to 48, and strongly suggests that the M53I mutation originated in Scotland. ..
- Aveyard J, Knowles M. Measurement of relative copy number of CDKN2A/ARF and CDKN2B in bladder cancer by real-time quantitative PCR and multiplex ligation-dependent probe amplification. J Mol Diagn. 2004;6:356-65 pubmed..We conclude that with appropriate controls RTQ-PCR is a sensitive and robust method to detect copy number changes in tumors even in the presence of contaminating normal cell DNA. ..
- Chaudru V, Laud K, Avril M, Miniere A, Chompret A, Bressac de Paillerets B, et al. Melanocortin-1 receptor (MC1R) gene variants and dysplastic nevi modify penetrance of CDKN2A mutations in French melanoma-prone pedigrees. Cancer Epidemiol Biomarkers Prev. 2005;14:2384-90 pubmed..21; P = 0.03] and dysplastic nevi (OR, 2.93; P < 0.01). Such results may have important consequences to improve the prediction of melanoma risk in families...
- Puri S, Si L, Fan C, Hanna E. Aberrant promoter hypermethylation of multiple genes in head and neck squamous cell carcinoma. Am J Otolaryngol. 2005;26:12-7 pubmed..028). Promoter hypermethylation of hMLH1, MGMT, and p16 genes was commonly detected in 47 SCCHN cases with up to 65% showing aberrant promoter hypermethylation in at least 1 ..
- Puig S, Malvehy J, Badenas C, Ruiz A, Jimenez D, Cuellar F, et al. Role of the CDKN2A locus in patients with multiple primary melanomas. J Clin Oncol. 2005;23:3043-51 pubmed
- Loo J, Paterson A, Hao A, Shennan M, Peretz H, Sidi Y, et al. Search for genetic variants associated with cutaneous malignant melanoma in the Ashkenazi Jewish population. J Med Genet. 2005;42:e30 pubmed
- Marian C, Scope A, Laud K, Friedman E, Pavlotsky F, Yakobson E, et al. Search for germline alterations in CDKN2A/ARF and CDK4 of 42 Jewish melanoma families with or without neural system tumours. Br J Cancer. 2005;92:2278-85 pubmed..We conclude that in the majority of Ashkenazi Jewish families, the genes tested are unlikely to be implicated in the predisposition to melanoma and associated neural system tumours...
- Niendorf K, Goggins W, Yang G, Tsai K, Shennan M, Bell D, et al. MELPREDICT: a logistic regression model to estimate CDKN2A carrier probability. J Med Genet. 2006;43:501-6 pubmed..These results represent the first-iteration logistic regression model to approximate CDKN2A carrier probability. Validation of this model with an external dataset revealed relatively robust performance. ..
- Hsu L, Lee H, Chau G, Yin P, Chi C, Lui W. Aberrant methylation of EDNRB and p16 genes in hepatocellular carcinoma (HCC) in Taiwan. Oncol Rep. 2006;15:507-11 pubmed..polymerase chain reaction (MS-PCR) was performed to analyze the promoter methylation status of the EDNRB and p16 genes in tumors and paired non-tumor liver portions of 34 HCC patients...
- Goldstein A, Landi M, Tsang S, Fraser M, Munroe D, Tucker M. Association of MC1R variants and risk of melanoma in melanoma-prone families with CDKN2A mutations. Cancer Epidemiol Biomarkers Prev. 2005;14:2208-12 pubmed..Additional studies are needed to confirm these findings and to explore the mechanisms that may contribute to this relationship. ..
- Raschke S, Balz V, Efferth T, Schulz W, Florl A. Homozygous deletions of CDKN2A caused by alternative mechanisms in various human cancer cell lines. Genes Chromosomes Cancer. 2005;42:58-67 pubmed..Aberrant RAG-mediated recombination may be responsible in T-ALL, and exuberant DNA repair by nonhomologous end-joining is the likely prevailing mechanism in SCCHN, but a distinct mechanism in TCC and glioma remains to be elucidated. ..
- Ulivi P, Zoli W, Calistri D, Fabbri F, Tesei A, Rosetti M, et al. p16INK4A and CDH13 hypermethylation in tumor and serum of non-small cell lung cancer patients. J Cell Physiol. 2006;206:611-5 pubmed
- Liu L, Broaddus R, Yao J, Xie S, White J, Wu T, et al. Epigenetic alterations in neuroendocrine tumors: methylation of RAS-association domain family 1, isoform A and p16 genes are associated with metastasis. Mod Pathol. 2005;18:1632-40 pubmed..044). Our study shows that in neuroendocrine tumors epigenetic alterations vary by tumor subsite and clinicopathologic features, including age of onset, histopathologic type and metastasis status. ..
- Kato A, Shimizu K, Shimoichi Y, Fujii H, Honoki K, Tsujiuchi T. Aberrant DNA methylation of E-cadherin and p16 genes in rat lung adenocarcinomas induced by N-nitrosobis(2-hydroxypropyl)amine. Mol Carcinog. 2006;45:106-11 pubmed..the involvement of aberrant DNA methylation in lung carcinogenesis by measuring expressions of E-cadherin and p16 genes, and their DNA methylation status in the 5' upstream region in rat lung adenocarcinomas induced by N-nitrosobis(..
- Ward R, Williams R, Law M, Hawkins N. The CpG island methylator phenotype is not associated with a personal or family history of cancer. Cancer Res. 2004;64:7618-21 pubmed..There is no justification for altering the personal or family cancer screening recommendations on the basis of tumor CpG island methylator phenotype status. ..
- Murphy J, Barrantes Reynolds R, Kocherlakota R, Bond J, Greenblatt M. The CDKN2A database: Integrating allelic variants with evolution, structure, function, and disease association. Hum Mutat. 2004;24:296-304 pubmed..We describe the database structure, content, current uses, and potential implications (http://biodesktop.uvm.edu/perl/p16). ..
- Cui X, Shirai Y, Wakai T, Yokoyama N, Hirano S, Hatakeyama K. Aberrant expression of pRb and p16(INK4), alone or in combination, indicates poor outcome after resection in patients with colorectal carcinoma. Hum Pathol. 2004;35:1189-95 pubmed..994, P <0.0001, respectively). Most CRCs demonstrate aberrant expression of pRb and/or p16 at resectable stages. Aberrant expression of pRb and p16, alone and in combination, heralds poor prognosis in patients with CRC. ..
- Daniotti M, Oggionni M, Ranzani T, Vallacchi V, Campi V, Di Stasi D, et al. BRAF alterations are associated with complex mutational profiles in malignant melanoma. Oncogene. 2004;23:5968-77 pubmed
- Huber J, Ramos E. The P48T germline mutation and polymorphism in the CDKN2A gene of patients with melanoma. Braz J Med Biol Res. 2006;39:237-41 pubmed..8%) or 540 C/T (6/27.3%), in the 3' untranslated region of exon 3. This result reinforces the idea that these rare polymorphic alleles have been significantly associated with the risk of developing melanoma. ..
- Chan P, Duraisamy S, Miller P, Newell J, McBride C, Bond J, et al. Interpreting missense variants: comparing computational methods in human disease genes CDKN2A, MLH1, MSH2, MECP2, and tyrosinase (TYR). Hum Mutat. 2007;28:683-93 pubmed..The results support the clinical use of computational methods as one tool to help interpret missense variants in genes associated with human genetic disease. ..
- Eliason M, Hansen C, Hart M, Porter Gill P, Chen W, Sturm R, et al. Multiple primary melanomas in a CDKN2A mutation carrier exposed to ionizing radiation. Arch Dermatol. 2007;143:1409-12 pubmed..A careful review of environmental exposures in these vulnerable cases may reveal cancer-promoting agents, such as ionizing radiation, that go unnoticed in less susceptible populations. ..
- Schiffman J, Hodgson J, VandenBerg S, Flaherty P, Polley M, Yu M, et al. Oncogenic BRAF mutation with CDKN2A inactivation is characteristic of a subset of pediatric malignant astrocytomas. Cancer Res. 2010;70:512-9 pubmed publisher..Taken together, these findings highlight BRAF as a frequent mutation target in pediatric astrocytomas, with distinct types of BRAF alteration occurring in grade 1 versus grade 2 to 4 tumors. ..
- Lopes E, Valls E, Figueroa M, Mazur A, Meng F, Chiosis G, et al. Kaiso contributes to DNA methylation-dependent silencing of tumor suppressor genes in colon cancer cell lines. Cancer Res. 2008;68:7258-63 pubmed publisher..Because Kaiso inactivation sensitized colon cancer cell lines to chemotherapy, it is possible that therapeutic targeting of Kaiso could improve the efficacy of current treatment regimens. ..
- Lee J, Lee C, Lee K, Lee C. Cross-talk between BubR1 expression and the commitment to differentiate in adipose-derived mesenchymal stem cells. Exp Mol Med. 2009;41:873-9 pubmed publisher..These effects occur independently of p16(INK4A) expression and may involve DNA methylation. Our results reveal a new and unsuspected feature of BubR1 expression in regulation of adult stem cell differentiation. ..
- Lesueur F, de Lichy M, Barrois M, Durand G, Bombled J, Avril M, et al. The contribution of large genomic deletions at the CDKN2A locus to the burden of familial melanoma. Br J Cancer. 2008;99:364-70 pubmed publisher..1% of total mutations in this series (1 of 48), confirming that they explain a very small proportion of CMM susceptibility. In addition, we excluded a new gene on 9p21, KLHL9, as being a major CMM gene. ..
- Ojima H, Saito K, Yamauchi H, Yamaki E, Idetu A, Hosouchi Y, et al. P16 protein abnormality in Epstein-Barr virus-associated gastric carcinomas. Anticancer Res. 2006;26:933-7 pubmed..5% (53 out of 65 samples) and 26.6% (46 out of 173 samples), respectively (p < 0.001). We suggest that the carcinogenesis of EBV-associated gastric cancers may be closely associated with a p16 abnormality. ..
- Wu C, Shan K, Zhou Y, Yang Q, Li C, Zhao Y, et al. [Research into methylation of p16 gene in the patients suffering from coal-burnt arsenism in Xingren County Guizhou Province]. Zhonghua Yu Fang Yi Xue Za Zhi. 2007;41:29-32 pubmed..1% of the healthy volunteers. There was statistical difference (P < 0.05) between them. Methylation of p16 gene CPG island should have important pertinence in the metabolism of coal-burnt arsenism. ..
- Sanz Ortega J, Roig F, Al Mousa M, Saez M, Munoz A, Sanz Esponera J, et al. 17p13 (p53 locus), 5q21 (APC locus) and 9p21 (p16 locus) allelic deletions are frequently found in oral exfoliative cytology cells from smoker patients with non-small-cell lung cancer. Histol Histopathol. 2007;22:541-5 pubmed publisher..Our study demonstrates that LOH studies can detect smoker patients with a mutated genotype in normal epithelial cells. Further prospective studies may confirm whether LOH studies can detect patients with a higher risk of NSCLC. ..
- Motokura T, Nakamura Y, Sato H. Aberrant overexpression of an epithelial marker, 14-3-3sigma, in a subset of hematological malignancies. BMC Cancer. 2007;7:217 pubmed
- Schmidt A, Kuhla B, Bigl K, Munch G, Arendt T. Cell cycle related signaling in Neuro2a cells proceeds via the receptor for advanced glycation end products. J Neural Transm (Vienna). 2007;114:1413-24 pubmed..Our results demonstrate that S100B and AGE may serve as mitogenic sources for the stimulation of neurons to progress through the cell cycle whereby signaling proceeds via RAGE --> p42/44 MAPK --> cyclin D(1)/cdk4. ..
- Levi B, Morrison S. Stem cells use distinct self-renewal programs at different ages. Cold Spring Harb Symp Quant Biol. 2008;73:539-53 pubmed publisher..This reduces stem cell function in aging tissues but also reduces cancer incidence. ..
- Ribeiro D, Fracalossi A, Uatari S, Oshima C, Salvadori D. Imbalance of tumor suppression genes expression following rat tongue carcinogenesis induced by 4-nitroquinoline 1-oxide. In Vivo. 2009;23:937-42 pubmed..Taken together, the results support the belief that the expression of Rb is closely event-related to malignant transformation and conversion of the oral mucosa, being a reliable biomarker linked to oral cancer pathogenesis. ..
- Sood A, Petersen H, Blanchette C, Meek P, Picchi M, Belinsky S, et al. Wood smoke exposure and gene promoter methylation are associated with increased risk for COPD in smokers. Am J Respir Crit Care Med. 2010;182:1098-104 pubmed publisher..These studies identify a novel link between wood smoke exposure and gene promoter methylation that synergistically increases the risk for reduced lung function in cigarette smokers. ..
- Popescu I. [Pre-neoplastic bronchial lesions: possibilities of diagnosis and chemo-prevention]. Pneumologia. 2008;57:201-8 pubmed..p53 and p16-INK4A genes seem to have the higher predictive value. Identification of these disturbances leads to improved possibilities of chemo-prevention. ..
- Buajeeb W, Poomsawat S, Punyasingh J, Sanguansin S. Expression of p16 in oral cancer and premalignant lesions. J Oral Pathol Med. 2009;38:104-8 pubmed publisher..89 and 0.17, respectively. No significant difference in the percentage of positive keratinocytes was found. As a marker, p16 is not reliable for oral mucosal dysplasia and malignant transformation. ..
- Zhang X, Soda Y, Takahashi K, Bai Y, Mitsuru A, Igura K, et al. Successful immortalization of mesenchymal progenitor cells derived from human placenta and the differentiation abilities of immortalized cells. Biochem Biophys Res Commun. 2006;351:853-9 pubmed..However, the differentiation potential was lost in these cells. This study reports a method to extend the life span of hPDMCs with hTERT and Bmi-1 that should become a useful tool for the study of mesenchymal stem cells. ..